One of the key features of a functioning immune system is its ability to distinguish antigens of foreign origin from those derived endogenously and to mount an immune response against the former. With respect to T cells, this goal is achieved through antigen recognition by T cell receptors (TCRs) and a highly ordered developmental process in the thymus and in secondary lymphoid organs. TCRs constantly sample diverse self- or foreign-peptide antigens presented in major histocompatibility complexes (MHCs) on the surface of antigen presenting cells (APCs) and elicit discrete intracellular signals and T cell responses. The mature T cell's response to antigens is largely dictated by the binding characteristics of its TCR for a given peptide-MHC complex. In general, peptide-MHC (pMHC) ligands with slower dissociation rates produce stronger TCR signals and lead to higher T cell reactivity to the antigenic peptides.
Variations in the antigenic peptide affinities to TCRs may lead to both quantitative and qualitative changes in its ability to activate TCR signaling pathways and T cell responses. Typically, the most stable pMHC complexes with respect to TCR binding are agonists, while the less stable variants are weak agonists and then antagonists, which are not able to activate T cells more than partially themselves and also block the response to agonist ligand. Although a number of models have been proposed to explain the kinetic discrimination in T cell activation, exactly how T cells sense quantitative changes in antigenic peptide affinities through their TCRs and produce both quantitatively and qualitatively different responses remains an intensive area of study.
In addition, T cell responsiveness and TCR signaling to a specific ligand also vary with different developmental stages, suggesting that T cell sensitivity to antigens might be intrinsically regulated during development. For example, in immature CD4+CD8+ double positive thymocytes, low affinity antigenic peptides that are unable to activate mature effector T cells are sufficient to induce strong activation and clonal deletion; antagonists that are normally inhibitory to effector T cells can induce positive selection. These observations demonstrate that T cell sensitivity is intrinsically regulated to ensure the proper development of specificity and sensitivity to foreign antigens while avoiding self-recognition. However, little is known about how intrinsic molecular programs are regulated, and how they influence T cell sensitivity toward antigens.
Methods of regulating T cell signaling thresholds and sensitivity to antigens is of great interest for clinical and research purposes. The present invention provides a means to regulate these functions.
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MicroRNAs (miRNAs) are an abundant class of non-coding RNAs that are believed to be important in many biological processes through regulation of gene expression. These ˜22-nt RNAs can repress the expression of protein-coding genes by targeting cognate messenger RNAs for degradation or translational repression. The mechanisms by which miRNAs exert these effects are unclear, as is whether they have any specific role in the adaptive immune response.
Chen et al. (2004) Science 303:83 describe the modulation of hematopoietic lineage differentiation by microRNAs. Krutzfeldt et al. (2005) Nature 438:685 describe the silencing of microRNAs in vivo with antagomirs.
The miR-181a RNA is represented in published US Patent Applications: 20060185027, Systems and methods for identifying miRNA targets and for altering miRNA and target expression; 20060134639, Method for the determination of cellular transcriptional regulation; 20060105360, Diagnosis and treatment of cancers with microRNA located in or near cancer associated chromosomal features; 20060099619, Detection and quantification of miRNA on microarrays; 20060057595, Compositions, methods, and kits for identifying and quantitating small RNA molecules; 20060019286, High throughput methods relating to microRNA expression analysis; 20050261218, Oligomeric compounds and compositions for use in modulation small non-coding RNAs; 20050260648, Method for the determination of cellular transcriptional; 20050256072, Dual functional oligonucleotides for use in repressing mutant gene expression.